7. Neurodegenerative disease

Question 1

Definition of neurodegenerative diseases

Answer 1

Progressive loss of specific groups of neurons or brain areas

Question 2

Incidence of neurodegenerative disease

Answer 2

> 65 years old higher incidence

Question 3

Main syndromes of neurodegenerative diseases

Answer 3

1. Dementia
2. Movement disorders
   - Parkinson disease (substantia nigra neurons)
   - Huntington chorea (basal ganglia)
3. Motor weakness
   - e.g motor neurone disease
4. Others
   - Spinocerebellar degenerations
   - Friedreich’s ataxia

Question 4

Epidemiology of Alzheimer disease

Answer 4

1. Aging population

2. 20% in > 80 yrs age group

Question 5

Molecular pathogenesis of Alzheimer disease

Answer 5

1. Chromosome 21 - APP (amyloid precursor protein) → production and deposition of beta amyloid peptides
2. Chromosome 19 - Apo E4 subtype → tau hyperphosphorylation

Question 6

Clinical features of Alzheimer disease

Answer 6

1. Progressive cognitive decline
2. Immobility
3. Pneumonia

Question 7

Pathology of Alzheimer disease

Answer 7

Abnormal protein deposition (Hippocampus, neocortex, amygdala)

1. Amyloid plaques (neuritic/senile plaques)
   - Collection of dilated, tortuous neuritic processes, often surrounding a core of amyloid (beta amyloid peptide)
2. Neurofibrillary tangles - hyperphosphorylated tau protein (within neurons)
   - → neuronal damage and loss

Question 8

Gross morphology of Alzheimer disease

Answer 8

Gross anatomy:

1. Smaller, atrophied brain
2. Temporal lobe most affected, also frontal and parietal regions

Histology

1. Neuritic (senile) plaques - extracellular amyloid deposits
2. Neurofibrillary tangles - intracellular filaments of tau protein

Question 9

Epidemiology of Parkinson disease

Answer 9

> 45 years old

Question 10

Pathology of Parkinson disease

Answer 10

1. Loss of nerve cells from substantia nigra (midbrain)
   - Contains neuromelanin
   - Reduced dopamine to the basal ganglia
   - Grossly: pallor in the substantia nigra
2. Lewy bodies in neurons

Question 11

Molecular pathogenesis of Parkinson disease

Answer 11

Disorder of alpha-synuclein gene → accumulation of alpha-synuclein protein: Lewy bodies

Question 12

Clinical presentations of Parkinson disease

Answer 12

1. Rigidity
2. Slowing of voluntary movements
3. Rest tremor

Question 13

Molecular pathogenesis of Huntington disease (chorea)

Answer 13

1. Autosomal-dominant
2. Mutations in the Huntingtin gene
   - increased trinucleotide repeats → Huntingtin protein accumulates in neurons of striatum (caudate nucleus, putamen), cortex
   - atrophy, neuronal inclusions
   - loss of striatal neurons → motor dysfunction
   - loss of cortical neurons → cognitive decline
3. Greater number of repeats → earlier age of onset
4. Spermatogenesis - repeated expansions → paternal transmission is associated with anticipation (early onset in the next generation)

Question 14

Morphology of Huntington disease (chorea)

Answer 14

1. Small brain with atrophy of the caudate nucleus and frontal lobe
2. Later: putamen and globus pallidus may be atrophied
3. Dilated ventricles

Question 15

Clinical features of Huntington disease (chorea)

Answer 15

1. Personality alterations, cognitive decline
2. Abnormal movements
3. 15 - 20 years average duration
4. Death from aspiration pneumonia, heart disease